What developmental biology tells us

Knowing about embryonic development is especially helpful in understanding the structure of the brain.

Fertilization, pre-embryonic development

Human pre-natal development traverses three stages:

• The first two weeks of human development are called the pre-embryonic stage;
• weeks 3-8, embryonic;
• and after that, fetal.

Let’s start at the beginning.

Of the tens of millions of human sperm ejected during intercourse, millions are destroyed by the acid environment (pH 3.8) of the vagina or trapped by gluey cervical mucus. Thousands more are killed by uterine leukocytes.¹Only strong sperm will make it. Force of numbers helps, too. The sperm follow the gradient of the chemical progesterone, which is released by the oocyte (egg). The surviving sperm usually meet the oocyte in the uterine (fallopian) tubes between the ovary and the uterus, since an unfertilized egg cannot live long enough to make the three-day journey along the tube. It is a question of force of numbers, as hundreds of sperm burrow through the oocyte’s outer protective cover, the corona radiata. Together, they release digestive enzymes from their tips to degrade both this layer and the inner layer, the zona pellucida. Finally, one sperm may manage to fuse its cell membrane with that of the oocyte so that it can release its DNA-containing nucleus into the oocyte. Then the work of the sperm is finished, as there exist mechanisms to prevent more than one sperm from fertilizing the oocyte. The process by which the haploid oocyte and the haploid sperm form a diploid zygote is rather more complicated than this, but that is the result.

Some time after fertilization, all the male mitochondria in the embryo are destroyed, leaving only the maternal mitochondria. It is not known how male mitochondria are recognized, but a gene has been identified, cps-6, which is imported into the male mitochondria and breaks them down. Since suppression of this gene leads to increased mortality in these embryos, there is certainly an evolutionary cause for the destruction, but it is not yet known.²How paternal mitochondria are destroyed in an embryo”, https://whyevolutionistrue.wordpress.com/2016/06/24/paternal-mitochondria-are-destroyed-in-an-embryo/.

The conceptus, the zygote and its containing membranes, takes three days to reach the uterus. Along the way, mitotic cleavage increases the number of cells, called blastomeres, but without increasing the total overall size. By the time the conceptus reaches the uterus, it is composed of sixteen compacted cells, together called a morula. Mitosis continues, soon making about 100 cells arranged in a dense shell around a fluid-filled cavity called a blastocoel. The conceptus is now called a blastocyst. The cells of the outer shell are called trophoblasts and will form structures like the placenta.. Within the cavity, other cells form an inner cell mass which will become the embryo.³Information in these paragraphs on fertilization comes mainly from Wolpert (2011) and Openstax Anatomy and Physiology, http://cnx.org/contents/FPtK1zmh@8.25:FwQJfRAS@3/Embryonic-Development.

During this time, the inner mass is composed of totipotent, or pluripotent, stem cells, which can differentiate to form any type of cell.

After a week, if all goes well, the blastocyst will attach to the inner uterine wall, the endometrium. In over half the cases, though, all does not go well and the blastocyst goes out with the menses. In successful implantation, the blastocyst eats through the endometrium, which then reforms so as to surround the embryo. The implantation marks the end of the pre-embryonic and the start of the embryonic state.

At the second week of embryonic development, the human zygote has developed into a two-layered embryonic disc contained between the blastocyst cavity (which will become the yolk sac) and the amniotic cavity. The ventral (forward) layer against the blastocyst cavity is the hypoblast. The dorsal layer against the amniotic cavity is the epiblast.

Gastrulation and embryogenesis – germ layer formation

At the third week, gastrulation takes place, converting the embryo from a two-dimensional disc into a complex three-dimensional structure formed of three germ layers. An indentation called the primitive streak forms along the dorsal (toward the back) surface of the epiblast. Growth factors produced by cells at the caudal (toward the posterior) end of the streak bring about cell multiplication. New cells migrate to the surface of the epiblast where they are specified as one of two new types, then migrate through the streak and form two new cell layers called germ layers.

• One layer, called the endoderm, pushes aside the hypoblast and comes to lie against the yolk sac. The endoderm will form the epithelial lining of the internal organs, among other things.
• A middle layer called the mesoderm is formed next to that. It will form the skeleton, muscles and connective tissues.
• The remaining epiblast cells become the third germ layer, the ectoderm. It will form the integumentary (skin) and nervous systems.

In chordates (such as us), as the neural streak shortens and disappears, it leaves behind a rod-like structure called the notochord. The notochord will later become the nucleus pulposus, the viscous inner core of the inter-vertebral discs that can cause such excruciating back pain when they function badly.

The mesoderm along the notochord forms paired lateral bulges called somites. Positional identity along this axis is furnished by our old friends the hox genes. As we have seen, these genes are expressed in the same order in the DNA as along the antero-posterior axis of the developing embryo. From the somites will develop the spinal column and its 33 vertebrae, as well as associated skeletal muscle.

Three mechanisms are important for these changes:

• Changes in cell shape are important in gastrulation and other processes. For instance, if a cell contracts on one side, it will become wedge-shaped. Joined to other cells with the same shape, an arc is produced, which is how a flat sheet of cells can bend. Such changes originate in the cytoskeleton.
• Cells have proteins on their surfaces which bind selectively to proteins on other cells, thus causing specific cells to adhere together. Different adhesive molecules cause different cells to adhere to one another.
• Cells can move relative to other cells by extending a long process called a filopodia, which is pushed out by elements of the cell cytoskeleton. The filopodia then move by a retraction mechanism similar to the one used by muscles to contract.

Neurulation – beginning of organogenesis and the nervous system

Soon after gastrulation, the rudiments of the CNS develop in the process of neurulation. Some cells of the ectoderm differentiate into neurepithelium and form a thickened area of the dorsal ectoderm called the neural plate. As shown in the figure, cells in the plate change shape and form a groove, the neural groove. The sides of the groove constitute the neural folds, which invaginate (grow out and come together to form a depression) and fuse, forming a neural tube. Cells along the tube change their adhesive properties so that the tube separates from the plate. The entire CNS will develop from the neural tube walls. The posterior part of the neural tube is formed differently, from a rod of cells which develop an interior cavity.

As the neural folds fuse, some ectoderm at the edges of the neural plate is squeezed off and is then situated between the neural tube and the ectoderm. This is called the neural crest and is the source of the entire PNS.

Organogenesis

By eight weeks after conception, the rudiments of all the basic organs have been set up. This is called organogenesis. Neurulation is the first important stage of organogenesis.

The three germ layers develop into different tissues as shown in the figure. Not shown are the development of bones from the mesoderm, or the development of the CNS from the ectoderm.

The following table shows a brief outline of embryonic development.

Week	Major events
4-5	The heart forms first as a tube, like the CNS, and starts beating around the beginning of week four. The liver starts to produce blood cells, a process which will later pass to bone marrow. Eye pits, limb buds and the beginning of the pulmonary system form.
6	Limb development starts in earnest.
7	Nostrils, outer ears and lenses form.
8	The major brain structures are in place. External genitalia are visible, but male and female are indistinguishable. Bone starts to take over from cartilage.

As it grows, the embryo folds so as to take on the familiar cylindrical shape, pointed at on end, with a primitive gut tube surrounded by the endoderm.

The organism is now at the stage of fetal development. From this point, we will restrict our interest to the consideration of nervous-system development.

Development of the nervous system

Some knowledge of the development of the nervous system is essential to understanding the structure of the brain.

The anterior neural tube develops into the brain. It is first differentiated into three sac-like primary vesicules, from front to back:

• the prosencephalon (forebrain)
• the mesencephalon (midbrain)
• the rhombencephalon (hindbrain), connected to the caudal neural tube.

As the prosencephalon begins to differentiate, two pairs of secondary vesicles grow on either side:

• the optic vesicles, which will eventually become the optic nerves and the retinas (so the retina is part of the brain); and
• the telencephalic vesicles, or telencephalon.

The remaining unpaired part of the prosencephalon is called the diencephalon, or “between brain”. The telencephalic vesicles grow out, then bend back over the diencephalon. From them grow another pair of vesicles, the olfactory bulbs. Cells within the telencephalon develop, forming new structures and axon systems. Spaces remain between the sides of the telencephalon and the diencephalon; they will fill with cerebrospinal fluid (CSF) and become the ventricles of the brain. The neurons within the gray matter of the telencephalon form the cerebral cortex and the basal telencephalon. The diencephalon differentiates into the thalamus and the hypothalamus. Axons from the developing forebrain extend to connect with other parts of the nervous system.⁴This brief summary is based on Bear, 178-192.

The hindbrain develops into the pons, medulla oblongata and cerebellum. In a coronal (side to side) section of the brain, it is easy to see how the telencephalon has grown down laterally to the diencephalon. The ventricles are also visible as dark areas.

The following diagram shows a somewhat more complete schema for the development of the human brain. The examples of development of germ layers are quite incomplete.

Next, let’s go to the next subject, the central and peripheral nervous systems.

The lymphatic system, constituted of the lymph vessels and nodes and the lymph, serves several functions.

A partial, parallel venous system

In the circulatory system, the heart pumps blood throughout the body via arteries, then smaller arterioles and finally through tiny capillaries, from which molecules are exchanged with cells and the rest of the body. Due to the pressure of the blood, much plasma is also released. The endothelial walls of the capillaries are just one cell thick and the spaces between them allow fluid to pass, but not the larger erythrocytes (RBCs), which therefore remain in the blood.

Outside the capillaries, the escaped fluid and molecules constitute the extracellular or interstitial fluid. It is composed of WBCs, including lymphocytes, some hormones, glucose and other molecules, such as proteins and lipids. Much of it is reabsorbed, but some remains outside. One of the jobs of the lymphatic system is to carry it back into the blood stream.

The lymphatic system therefore can be considered a parallel path to the venous system, but it carries no RBCs, only WBCs, called leukocytes. The lymph, as the fluid is called when it is inside the lymphatic system, is returned to the veins at two ducts placed strategically where blood pressure is relatively very low and the liquid can therefore be inserted into the vein easily.

Lymph is not pumped by the heart. Smooth muscles in the walls of the lymph vessels, as well as skeletal muscle, squeeze the lymphatic vessels, pushing the lymph through one-way valves which prevent its returning to the capillaries. Similar valves allow the interstitial fluid to enter the lymph vessels but not to leave them. Lymph flows from lymphatic capillaries, or terminal lymphatics, and into bigger lymph vessels before re-entering blood veins in either the right lymphatic duct (which drains the upper right-hand side of the body) or the thoracic duct (which drains all the rest).

Immune system function

The lymphatic system is much more than a simple alternate return route for WBCs. Since it carries lymphocytes, it is crucial for the immune system. Scattered about the body along the lymphatic vessels are some 500-600 special tissues (too small to be called organs) called lymph nodes, in which immune-system cells do much of their work.

There are macrophages present in all tissue, but most of the immune-system cells spend their off-duty hours in the lymph nodes. The complicated process of B-cell and T-cell growth and activation (to be discussed in the next section) is carried out more rapidly in an environment where macrophages or dendritic cells and B and T cells proliferate and this is in the lymph nodes. The large number of such cells, as well as macrophages and others, means that the lymph passing through the node has most if not all its pathogens filtered out and phagocytozed.

The spleen is not connected to the lymphatic vessels, but It contains a large number of macrophages and dendritic cells which carry out a similar filtering process not on lymph, but on the blood.

Other secondary lymphoid tissues are:

• lymphoid nodules, such as the tonsils, in the respiratory and digestive tracts, which contain dense clusters of lymphocytes;
• mucosa-associated lymphoid tissue (MALT);
• bronchus-associated lymphoid tissue (BALT).

Function with other molecules

Glucose in the small intestine diffuses out of the intestine, into capillaries and thence throughout the the body through the circulatory system. But lipids leave the small intestine in the form of chylomicrons, which are too large to enter capillaries. However, they can enter the lymphatic system lacteals, lymphatic capillaries in the intestinal villi. The lymphatic system then conveys the lipid-bearing chylomicrons into the blood.

In a similar way, other molecules, such as some hormones, or waste products, being sent to the liver or kidneys, and which are produced not in the blood but elsewhere in the body, may not be able to enter blood capillaries, and so flow into the circulatory system via the lymphatic system.

Now we go on to the immune system.

The immune system is complex, multi-leveled and multi-component.¹Its complexity and numerous components, which are not independent or separable for study, has led to confusion in the designation of its sub-systems. (Author’s opinion.) Even though much has been learned about it in recent decades, it is still under intense investigation.

Rather than starting out with lists of the components, the structures and so forth, let’s look at an example.

Overview – physical barriers and inflammation

Suppose something bad – a virus or a mean bacteria – gets into a body. What happens then to protect against this pathogen?

The first line of defense against pathogens is largely mechanical or chemical. It comprises such things as the skin, which forms a natural barrier to keep things out; the mucus in our respiratory system, which captures microbes in the air we breathe and, by means of tiny hairs – cilia – drags them back up to where we can swallow them²Yuk.; and the gastrointestinal system, which is highly acid and can therefore kill many invaders.

But some of the invaders get past these barriers. And some do not even need to, because they show up internally. And tissue damage can result from external sources also, as when a hammer is injudiciously applied to a thumb. So after the barrier layer, what then?

The next step is often inflammation, called the inflammatory response. The infected area turns red, swells up, becomes hot and hurts. This region is the battlefield where the fight carries on after the barriers have been breached. This is where the various cells of the immune system go about protecting us.

Injured cells call for help by releasing chemical messengers called chemokines into the interstitial fluid. These indicate to cells farther away that there is a problem to be solved and implores their assistance. The cavalry arrives not by following a trumpet call, but by moving against the gradient of the chemokines, toward their point of greatest concentration, in a process called chemotaxis.³Neutrophil to driver: “Follow that pathogen!”

Among those coming to help, mast cells are one of a group of cells which contain granules, from which they release histamine, leukotrienes and prostaglandins. These chemicals cause vasodilation: Blood vessels expand so more blood can come in, bringing help, but they also become porous. Increased blood flow and plasma leakage into the interstitial space are responsible for the heat and redness and painful swelling. 

Chemokines also lure in phagocytes to surround and absorb pathogens. The first ones to arrive are neutrophils, the most plentiful phagocyte in the body. Other phagocytes — macrophages and dendritic cells — come to phagocytize pathogens,  to engulf them and destroy them in the process of phagocytosis.. All the cells mentioned so far are part of the non-specific or innate response. They are non-specific because each of them may act against any pathogen. Because they all rush in, they operate quickly, but they are neither very precise nor efficient.

Now we reach the next level of the immune system, the specific immune system, or adaptive immune response, as B cells and T cells begin to do their thing.

Any invading organism consists of at least one compound — in it or on it — which can be used to identify it uniquely. These compounds are called antigens, from antibody generations. The adaptive response depends on these markers to distinguish one pathogen from another. Phagocytes, like macrophages. dendritic cells or B cells, extract the antigens from the pathogen itself and display them on their own surface. This enables a specific response, one depending on the identity of the pathogen. Such a series of events takes more time than the innate response, but because it is specific to the particular pathogen, it is usually more effective.

Macrophages which display antigens on their surface serve as messengers or links between the innate and adaptive responses and begin the intricate process by which B cells, with the collaboration of T cells, produce antibodies, which can protect us over time.

The complement system is composed of proteins which aid immune response. They may, for instance, bind to a pathogen and thus label it – opsonization – calling attention to it so that phagocytes will deal with it. The complement system can help out both the non-specific and specific responses.

Now let’s look at these different immune-system components in more detail.

Innate immune response

The innate, or non-specific, immune system depends on several types of cells. It most likely evolved before the adaptive immune response.

One group of cells is constituted of phagocytes, which can engulf and contain pathogen cells, a process called phagocytosis. The contained pathogen, called a phagosome, is usually killed by a lysosome in the phagocyte cell. A phagocyte recognizes pathogens in a somewhat approximate way, as its surface (not to mention its genes) can contain only a certain number of antigen pattern recognition receptors (PRRs). Phagocytes are also important because they represent the first step in the process which identifies pathogens and leads to the release of specific antibodies. There are several phagocytes associated with the innate immune response.

• A macrophage is an amoeba-like phagocyte which can squeeze through tissues and capillary walls. It is capable of phagocytozing quite large bacteria.
• A neutrophil is a spherical phagocyte summoned from the blood stream. It is a granulocyte, meaning that it contains granules of substances such as histamine. It is the most abundant of the white blood cells (WBCs).
• A dendritic cell is an irregularly shaped cell with many appendages looking like the dendrites on neurons, hence the name. However, they are not neurons. Although they may be partly phagocytotic, their principal function is as antigen-presenting cells, about which more very soon.
• A monocyte is a precursor cell which may mature into either a macrophage or a dendritic cell.

A natural killer cell (NK) is not generally cosidered a phagocyte, but it is capable of convincing a pathogen cell to commit suicide, or apoptosis. It may do this through the use of a special ligand or by releasing perforin to bore a hole in the cell wall and then cause granzyme to enter the cell and bring about apoptosis.

Antigen-presenting cells (APCs)

The mechanisms of antigen presentation are somewhat complex. T cells, an essential part of the adaptive immune system, recognize antigens only when they are presented on the surface of antigen-presenting cells (APCs). APCs internalize the pathogen or antigen, break It up and bind pieces of it with a protein called the major histocompatibility complex (MHC) molecule. Only when the complex formed by the MHC molecule and the antigen is presented on the surface of the APC can it be recognized by T cells.

There are two types of MHCs and so two types of APCs.

• The so-called professional APCs are the innate-response macrophages and dendritic cells as well as the adaptive-response B cells, all of them cells of the immune system. When such a cell phagocytizes an external pathogen, it associates pieces of the antigens with MHC class II (MHC II) molecules and displays the complex on its surface. 
• Non-professional APCs include all nucleated cells in the body.⁴Reminder: red blood cells lose their nuclei. They are not phagocytes, but they nevertheless display class I MHC (MHC I) complexes of internal pathogens, such as viruses which have reproduced within the cell.

Professional APCs can display MHCs of both classes, depending on whether the pathogen is internal (MHC I) or external (MHC II).

Leukocytes, lymphocytes and WBCs

Blood cells are all differentiated from hematopoietic stem cells. For granulocytes like neutrophils, this occurs only in the marrow of bones . But lymphocytes and plasma cells are produced in lymphogenous material, which exists in lymph glands and other areas, including bone marrow

Erythrocytes are red-blood cells, of which the adults contain no nuclei, and platelets are responsible for blood clotting. The other cells shown are all WBCs, or leukocytes. In the lymphatic system, they are called lymph. They also constitute the interstitial fluid between cells.

Dendritic cells are special, existing in several varieties, and can come from a myeloid or a lymphoid precursor, not shown in the figure.

NK cells, B cells and T cells are called lymphocytes. Whereas the NK and B cells mature in bone marrow, T cells migrate to the thymus for maturation. NK cells are part of the innate immune system. B and T cells are cells of the adaptive immune system.

Each instance of a B or T cell has surface receptors which can be activated by only one type of antigen. Therefore, in order to detect almost any pathogen, B‑cell and T‑ell receptors exist in souch a great number of variiants that it would be impossible for so many genes to exist in their DNA. This difficulty is overcome by means of an astounding technique – gene shuffling. During the expression of their genes, segments of genes are shuffled like cards, giving over 1011 possible combinations, each of which detects a specific antigen.⁵Isn’t this amazing?

After strong selection against cells which may attack their own organisms, both types of cells migrate to lymphoid tissue throughout the body.

When a macrophage phagocytizes a pathogen, it passes antigens on to the lymphocytes. When a lymphocyte receives its specific antigen, it becomes activated and reproduces abundantly. (B cells also require the help of special T cells, as we shall see in a moment.) Activated B cells produce antibodies. Groups of antibodies or T cells activated by and sensitive to a specific pathogen are called clones.⁶A clone is not a simple copy, it is a set of copies sensitive to a specific antigen. Cells of a clone therefore share the same antigen receptors. Only lymphocytes which are activated by an antigen reproduce and multiply into clones, so the process can be seen as one of natural selection. Only activated cells survive and reproduce.

Adaptive immunity

Now for more details. I find this subject easier to understand by proceeding from less complex to more, so I will start with B cells, which will leave them partly unexplained until T cells have been discussed.

Humoral response – B cells and antibodies

When a “naive” B cell leaves the bone marrow or the lymphatic system and binds to an antigen, its ctivatiion process has begun. Part of the antigen is internalized, broken up and displayed on the cell’s surface in an MHC II complex. When this is bound by a type of T cell called a Th2 cell (the part that is left until later, but not much), the B cell is completely activated. (Some B cells are T-cell independent and do not require such activation.) The B cell then is duplicated into sets of clones to make many B cells of two types – effector cells and memory cells. The effector cells, now called plasma cells (not to be confused with blood plasma, which is mostly water) release a form of their surface receptors called antibodies, or immunoglobins (abbreviation Ig), into the environment.

The immunity conferred by antibodies is called humoral immunity. Each antibody recognizes only the antigen specific to its parent B cell. When antibodies – immunoglobins – encounter a pathogen carrying this antigen, they bind tightly to it via a lock-and-key mechanism based on their respective shapes and thus prevent the pathogen from doing any harm. They also signal phagocytes to absorb and kill the pathogen (opsonization again).

The memory cells wait around until they die or are needed again to clone and produce more receptor and memory cells. Some of them remain available for years or even decades. When needed, they allow for a much more rapid response to subsequent infections, called secondary response, as opposed to the initial, primary response. In secondary response, B cells as plasma cells are already available for producing antibodies without going through all the rigmarole of APCs and being activated by a T cell. We will look at why this takes place later.

Antibodies exist in five classes, imaginatively called, IgA, IgD, IgE, IgG and IgM.

• Only IgM and IgD function as receptors on a B cell; IgD remain on the B cells.
• IgM can leave the B-cell surface. They are the largest of the Igs, having 10 binding sites, whereas IgA has four and the others only two. So IgM is an excellent binder, especially during the early part of a primary response. In the latter part of the primary response, IgM can undergo a process of class switching in which it changes to a class IgG, IgA or IgE.
• IgG is the most common (80% of antibodies in serum) and is the most important antibody in secondary response. It also is the only one which can cross the placenta to protect the fetus.
• IgA has two forms. The eight-chain structure moves into mucous membranes and so is the only antibody to leave the interior of the body. The four-chain form remains in the blood.
• IgE is very rare. It serves to make mast-cell degranulation specific. In doing so, it contributes to allergies.

Cell-mediated response – T cells

Like B cells, T cells exist in some 10¹¹ possible versions, each receptive to a specific antigen. But T cells are more complex (which is why we left them until now), being of two types, one of which has sub-types.

T cells can not detect antigens directly; they can only detect those which are displayed on the surface of APCs. Just as there are two types of APCs, according to their MHC type, there are two types of T cells. Certain glycoproteins on T cells are called clusters of differentiation, or CDs. On leaving the thymus, most T cells have either CD4 or CD8 and so are called CD4⁺ or CD8⁺.

• CD4 is a co-receptor which enables so-called helper T cells, or Th cells, to recognize class II MHCs on APCs, including those on B cells.
• CD8 is specific to MHC I and to cytotoxic T cells, also called Tc cells.
• There is a third type, called Treg, for regulatory T cell, with CD4 and CD25.

Tregs are less well understood, but suppress immune response by other T cells in certain cases.

Of the two principal types, those simpler to understand are the CD8+ cells, called cytotoxic T cell or Tc cells when they are activated. As in the case of B cells, activated T cells multiply into sets called clones and while some of these become memory T cells, awaiting the next infection, the others become effector T cells. Effector T cells destroy infected cells by inducing apoptosis, like NK cells.

The other main type of T cell is the helper T cell, or Th, which exists in two versions, Th1 and Th2, the difference being mainly in the type of cytokines they secrete. Cytokines are short-distance signaling molecules. Those secreted by Th1 act as an alarm signal and promote phagocytosis. Alas, helper T cells are damaged by the human immunodeficiency virus (HIV).

Th2 is the one we have been putting off and which allows the B cell to do its job of distributing antibodies. In order to have any effect, a Th2 cell must recognize its own antigen type on a B cell’s class II MHC. When this happens, the Th2 cell secretes cytokines which, when detected by the B cell, complete activation of the B cell, so that it may clone to memory cells and antibody-emitting effector cells. A possible reason for the complexity of this procedure will be explained shortly.

Quick (?) overview

Let’s do a run-over of the humoral immune system, the creation of antibodies⁷Remember, we use the words immunoglobin and antibody to refer to the same things.:

• A phagocytic cell of the innate immune system, such as a dendritic cell, phagocytozes a pathogen. It presents antigens from the pathogen on its surface in MHC II complexes.
• A B cell of the adaptive immune system whose membrane-bound immunoglobins are of a specific type happens to meet the same type of pathogen and also phagocytozes it and presents its antigens on its surface in MHC II complexes.
• Both the dendritic cell and the B cell are now APCs for the specific antigen. These two steps could have occurred in either order.
• A helper T cell for the same type of antigen bumps into our dendritic cell, binds to the MHC II complex and becomes activated.
• If the activated cell is a type Th1, it starts emitting cytokines as an alarm and to promote phagocytosis.
• If the activated cell is a type Th2, it may later meet our B cell and bind to its MHC II complex. It then release cytokines which complete activation of the B cell.
• The activated B cell duplicates itself into clones of two types, effectors and memory cells, the former being plasma cells which emit numerous immunoglobins – antibodies.
• The antibodies cling to their specific pathogens and render them harmless. At the same time, they tag them for phagocytosis.

That was the case for an external pathogen. But some pathogens, like cancers, may occur internally or, like viruses, penetrate into the cell before being noticed. Since all nucleated cells may present MHC I complexes, these will be recognized by CD8+ cells which are activated to cytotoxic T cells which will act to kill the offending (or offended) cell.

Once activated, all B and T cells duplicate to form clones of numerous effector cells and memory cells.

Why so complicated? – auto-immunity

Why do B cells have to go through a process of being activated by T cells (which have to be activated by APCs…) before producing antibodies in the primary response? One answer is to avoid auto-immunity.

Auto-immunity is when your immune system mistakes some essential part of you for a pathogen. This can lead to some really awful conditions like AIDS, lupus or myasthenia gravis. Since the receptors on B and T cells are the result of gene shuffling, many combinations will occur which could lead to auto-immunity. This is avoided in two ways:

1. Under the assumption that pathogens are rare within the bone marrow and the thymus, any B or T cells which activate inside them are killed before they can get out and do any harm.
2. The probability that either a B or T cell released into the body be an auto-immune cell is small (because of step 1), The process of requiring that a T cell “vet” the activation of a B cell through the APC process means that the total probability of generating an auto-immune cell is something like the product of the individual probabilities and therefore very low indeed.

So the requirement that B cells be activated by their corresponding activated T cell is a way of avoiding auto-immunity. Nevertheless, however low the probability, some auto-immune diseases do occur … alas.

Now on to embryonic development, how that sperm and egg made us.

We will consider the circulatory system only from a relatively high-level (undetailed) view of its structure and function – as a kind of plumbing system. This consists of several parts – the pump (the heart), the pipes (the veins and arteries) and the fluid (the blood).

The heart as pump – circulation

The heart consists of four chambers, two smaller, upper chambers – the atria (singular atrium) – and two larger, lower ones – the ventricles.

Even though we already indicated in the chapter on bioenergetics the general flow of blood through the heart and the cardiovascular circulatory system. it is worth repeating.

Oxygen-depleted blood from the body enters the right atrium of the heart and is pumped into the right ventricle and thence through the pulmonary artery into the lungs. (The figure is somewhat confusing because the lungs are shown above the heart, about at the place of the brain.) After picking up oxygen in the arterioles of the lungs, the blood returns through the pulmonary vein into the left atrium of the heart. It then is pumped into the left ventricle and out into the body. In capillaries, oxygen passes into cells and the oxygen-depleted blood is then returned to the right atrium through veins and either the superior or inferior vena cava.¹Remember, veins flow towards the heart, whether they contain oxygenated blood or not. Four valves – the mitral, tricuspid, pulmonary and aortic – keep the blood from flowing back in the wrong direction.

The walls of the heart are composed of three layers of tissue, of which the most important is the myocardium. This is the muscle which contracts to squeeze the four chambers and force blood through the heart and out into the lungs or body. Being mostly muscle, the heart itself requires energy and nutrients and, so, blood. This is supplied by the coronary arteries branching off the aorta, the main exit for oxygenated blood. The heart pumps blood to itself.

Electricity in the heart

Where study of the heart becomes really interesting is its electrical operation, where we meet our old friends energy and communications again.

The big question is, “What makes the heart beat?” Surprise: The commands to make it do so do not come from the brain. The brain can only modulate the rate of heartbeat.

The generation of an electrical signal to make the heart beat, i.e., to cause its muscles to contract in a rhythmic and well-synchronized manner, takes place in the sinoatrial (SA) node (or SAN, or sinus node) in the wall of the right atrium near the entrance of the superior vena cava. (See following figure.) Although similar signals may be generated elsewhere in the heart, they are usually overwhelmed by the higher-frequency SA signal. Like most cells in the body, the cell membranes of heart muscle contain a number of structures for allowing – or requiring – substances to enter or leave the cell. (We considered this in the biochemistry chapter.) Among these are Na/K pumps which maintain a negative voltage inside cell walls. In the SA node, however, instead of a voltage of around -80 Mv, slow leakage limits the voltage to -55-60 mV.

Heart beat is caused by the generation of an action potential in the SAN.

The initial increase of the SAN membrane potential from its minimum, rest potential, is due mostly to leakage channels which allow some Na+ to enter the heart, gradually raising the membrane potential from about -60 mV to -40 mV (the “prepotential” in the figure). This is the threshold value for a gated channel to open, allowing depolarization of the cell. However, because of the leakage, only slow Na⁺–Ca⁺⁺ channels are opened, which explains the relatively slow rise of the potential. (The slow rate of potential rise from -40 mv to 10 mv is not obvious in the figure.)

After about 100-150 milliseconds, the Na⁺–Ca⁺⁺ channels close and K⁺ channels open. As K⁺ rushes out of the cell, the potential redescends to a bit under its initial resting value. Then the K⁺ channels also close and the cycle starts over. The result is that the heart beats all by itself due to the membrane potential of the cardiac muscle cells, the slow leakage of Na+ and the voltage-gated Na⁺–Ca⁺⁺ and K⁺ channels.

The action potential generated in the SAN passes into atrial muscle fibers which contract and squeeze the atria. The action potential travels through the atria and down to the atrioventricular node (AV node), near the floor of the right atrium. A delay takes place here which keeps the ventricles from contracting at the same time as the atria. The action potential then passes into the bundle of His, which separates into two different paths, the left and right bundle branches, which lead to the Purkinje fibers wrapped around the ventricles.

So far, we have only talked about the form of an action potential in the conducting cells. When it reaches the contracting cells, which actually make the muscles squeeze the blood along its way, the form of the action potential is different.

The ventricular contracting action potential is shown in the above figure. Since resting ventricular potential is around -90 mV, the fast Na+ channel opens to initiate a fast depolarization. Then the fast channel closes but the slow Na+–Ca++ channels open, maintaining the potential at a plateau until they close and the K+ channels open, repolarizing the cell. This long plateau, or refractory period, of about 200 ms allows time for blood to flow and avoids premature contractions which would disrupt the synchronism of the contractions.

The cardiac cycle

The heart’s electrical signals can be detected on the surface of the skin by an electro-cardiogram (ECG or sometimes EKG) and show the patterns of atrial and ventricular systole (contraction to pump blood out of the heart) and diastole (relaxation while the chambers refill with blood). The output shows cycles of the heart’s functioning over several steps, called the cardiac cycle. It goes like this:

1. All chambers are relaxed (diastole) and blood flows into them, filling them to about 70-80% of their capacity. Valves keep the blood from flowing in the wrong direction.
2. Depolarization in the SA node starts a series of action potentials which cause atrial contraction (systole) which forces the rest of the blood into the ventricles, filling them completely. This is shown as what is called the P wave on the ECG output. The signal moves down to the AV node, where there is a delay. After about 100ms,the atria relax and enter their diastole phase. They have now completed their activity for this cycle.
3. The action potential moves down through the bundle branches and through the Purkinje fibers, launching ventrical systole. The signal reaches the right ventricle first, so it starts to contract slightly before the left. The increased pressure closes the tricuspid and mitral valves to the atria and opens the pulmonary and aortic exit valves (semilunar valves). Blood flows out to the lungs and the body. This stage shows up on the ECG as the QRS complex and lasts about 270ms. Blocks in the branches which impede the signal for whatever reason alter the form of the QRS signal.
4. The ventricles relax into diastole at the T wave. Ventrical diastole lasts about 430ms.

The cycle starts over – constantly, all the time we are alive, from our heart’s formation during embryonic development to our last moment of life.

The “lub-dub” sound of a heartbeat, familiar to doctors with stethoscopes and to horror-movie fans, corresponds to the opening and closing of the semilunar (aortic and pulmonary) valves and so to the beginning and the end of the ventricular systole.

Regulation of heart rate

Adding up the durations of the phases indicated above gives 100+270+430 = 800ms per heartbeat, or 75bpm (beats per minute), the average rate for an adult. Although the heart itself is responsible for its beating, both the heart contraction rate (HR) and the volume of the chambers (stroke volume, SV) are influenced in several ways.

Nervous system influence on the heart originates in cardiac centers of the medulla oblongata of the hindbrain, just in front of the cerebellum. Nerve fibers from this region reach several parts of the heart, including the SA and AV nodes and both atria and ventricles. The sympathetic nervous system (e.g., “fight or flight”) releases norepinephrine (NE) which speeds up the heart rate. The parasympathetic system sends acetylcholine (Ach) along the vagus nerve which slows the heart rate. At rest, both (but mostly the parasympathetic) contribute to autonomic tone, which would otherwise be about 100bpm.

Increased physical activity detected by proprioreceptors, changes in blood pressure or flow detected by barioreceptors (stretch) or metabolic activity detected by chemoreceptors send data to the cardiac centers which then regulate heart beat and flow appropriately. Hormones, ion concentrations, temperature, pH and stress (via the limbic system) all have an influence.

Bear in mind that the heart is a muscle and, like the other muscles, needs regular exercise.

The blood

The production of blood and lymphatic system cells from hematopoietic stem cells is shown in the section on the immune system. However, the blood contains other components, listed in the table in the following figure.

Biologists distinguish four types of tissue:

1. epithelial tissue (epithelium) covers surfaces, inside the body and out;
2. connective tissue provides binding, support, protection and integration;²To my mind, connective tissue is “all the rest”.
3. muscle tissue contracts and consists of three types: skeletal (voluntary), smooth and cardiac;
4. nervous tissue propagates electrochemical signals.

Blood is considered to be connective tissue.³Obviously, it is not one of the others. Connective tissue consists of cells which are relatively far apart, compared to epithelial cells, and which are dispersed within a matrix, usually a liquid. The cells of blood, called the formed elements, float in an extracellular matrix called plasma, which is mostly water. The components of blood are shown in the following table.

Although blood plasma is about 92% water, it does contain three types of plasma proteins as well as small amounts of other substances.

Aside from water, the major components of the plasma are albumin and and globulins. Albumin binds to lipids and transports them through the hydrophilic plasma. It also serves to regulate osmotic pressure. Globulins, or gamma globulins, are immunoglobins, i.e., antibodies, about which more shortly.

Blood serves many purposes, but the most important (although it could not go on without the others) is the transport of oxygen, nutrients and waste matter, such as carbon dioxide.

The transport of oxygen is carried out by erythrocytes, or red blood cells (RBC), which make up 99% of the formed elements. They are so numerous, they make up approximately 25% by number of all the cells in the body.

As an erythrocyte develops in the marrow of large bones, it ejects most of its organelles, including the nucleus and the mitochondria. Without mitochondria, it is only capable of anaerobic respiration, which prevents its using up the very oxygen it is transporting. Erythrocytes are shaped like tiny disks, thinner in the middle, which enables them to fold up to fit through small openings in capillary walls. They are extraordinarily well adapted to their function. For instance, the absence of many internal organelles leaves more space for the molecule which transports oxygen: hemoglobin.

A molecule of hemoglobin is made up of four folded protein chains called globin, each one of these attached to a red pigment molecule called heme, which contains one ion of iron, Fe²⁺. To each iron ion, one molecule of oxygen can bind for transport, making four oxygen molecules per hemoglobin molecule. The result is called oxyhemoglobin and constitutes the bright red blood which flows in non-pulmonary arteries and pulmonary veins. The oxygen-transporting capacities of the body’s hemoglobin are quite phenomenal. One erythrocyte contains about 300 million hemoglobin molecules and so binds up to 1.2 billion oxygen molecules.

Even so, there are not too many. If the number goes down, we suffer from anemia, if not something worse. The composition of hemoglobin underlines the necessity of small amounts of trace elements like iron in the body.

The amount of oxyhemoglobin is in equilibrium with the milieu:

• A higher concentration of oxygen leads to a greater amount of oxyhemoglobin formed;
• a lower concentration of oxygen causes oxyhemoglobin to dissociate into oxygen and hemoglobin.

This explains why oxyhemoglobin forms in the oxygen-rich lungs and dissociates in the capillaries where oxygen is less concentrated. In addition, the presence of CO₂ in the blood somewhat increases the dissociation of oxyhemoglobin.

Next, the lymphatic system.

The endocrine system, consisting of all hormone-synthesizing tissue, works together with the nervous system to regulate bodily processes. Hormones, which are endogenous (produced within the body), are far more numerous than those only produced by glands. Also, one neurotransmitter, norepinephrine, functions sometimes as a hormone and sometimes as a neurotransmitter.

Hormones are of four types:

• lipid (or steroid) hormones – like estrogen, testosterone or cortisol, all made from a lipid, cholesterol;
• peptide hormones – made of short chains of amino acids; include anti-diuretic hormone (ADH) and oxytocin;
• glycoprotein (or protein) hormones – made of longer chains of amino acids; includes thyroid-stimulating hormone (TSH);
• amine hormones – formed from the amino acids tryptophan or tyrosine; examples are melatonin, thyroid hormones, epinephrine and norepinophrine, and dopamine.

In order to have an effect, hormones must activate specific receptors on cells. A cell’s receptivity depends on the number of receptors on the cell and this can vary with time (up– or down-regulation) in response to too few or too many hormones in the blood stream, an example of the feedback control of hormonal effects.

Reception can happen in two ways. Lipid hormones are hydrophobic and therefore capable of crossing cell membranes, whereas the other three types can not. But since blood is water-based, lipid hormones must bind with a transport protein in order to travel through it. This procedure significantly increases the lifetime of the lipid-transport complex. Lipid hormones then cross the cell membrane into the cytoplasm where they bind with a receptor in the cytoplasm. The receptor-hormone complex moves into the nucleus and activates the expression of an appropriate gene to manufacture a protein which may lead to the desired result.

The other three types, non-steroid hormones (called first messengers, in this case), can travel freely through the blood, but cannot cross the cell membrane and so must bind with a receptor on the outside surface of the membrane. This begins a cascade of signals. A G protein is activated which in turn excites the so-called second messenger (usually cAMP1). Some steps later, a protein is activated by phosphorylation (addition of a phosphoryl radical) and this may lead to a cascade of many different effects, including synthesis of other products.

So steroid (lipid) hormones hitch a ride through the blood and then enter the cell to activate gene expression. Non-steroid hormones move freely through the blood, but pass the message by knocking at the cell’s door and transmitting the message to a second messenger which is already inside. 

Now let’s break it down some and take a look at some of the more important or interesting components of the endocrine system.

The following table gives some information about the principal hormones.¹Table after Openstax College, http://cnx.org/contents/FPtK1zmh@8.24:4lDC0JfF@3/An-Overview-of-the-Endocrine-S, with some modifications. We will then consider some examples.

Source	Hormones	Class	Effect
Pituitary (anterior)	Growth hormone (GH)	Protein	Growth of tissues
Pituitary (anterior)	Prolactin (PRL)	Peptide	Milk production
Pituitary (anterior)	Thyroid-stimulating hormone (TSH)	Glycoprotein	Thyroid hormone release
Pituitary (anterior)	Adrenocorticotropic hormone (ACTH)	Peptide	Adrenal cortex hormone release
Pituitary (anterior)	Follicle-stimulating hormone (FSH)	Glycoprotein	Gamete production
Pituitary (anterior)	Luteinizing hormone (LH)	Glycoprotein	Androgen production by gonads
Pituitary (posterior)	Antidiuretic hormone (ADH)	Peptide	Water reabsorption by kidneys
Pituitary (posterior)	Oxytocin	Peptide	Uterine contraction, lactation
Thyroid	Thyroxine (T4), triiodothyronine (T3)	Amine	Basal metabolic rate
Thyroid	Calcitonin	Peptide	Reduce blood Ca++ levels
Parathyroid	Parathyroid hormone (PTH)	Peptide	Increase blood Ca++ levels
Adrenal (cortex)	Aldosterone	Steroid	Increase blood Na+ levels
Adrenal (cortex)	Cortisol, corticosterone, cortisone	Steroid	Increase blood glucose levels
Adrenal (medulla)	Epinephrine, norepinephrine	Amine	Fight-or-flight response
Pineal	Melatonin	Amine	Regulate circadian rhythm
Pancreas	Insulin	Protein	Reduce blood glucose levels
Pancreas	Glucagon	Protein	Increase blood glucose levels
Testes	Testoserone	Steroid	Development of male secondary sex characteristics, sperm
Ovaries	Estrogens and progesterone	Steroid	Development of female secondary sex characteristics, preparation for childbirth

The hypothalamus and the pituitary gland

The hypothalamus-pituitary complex is indeed complex. The hypothalamus, in the brain, receives signals from many parts of the nervous system. Any imbalance or non-optimal signal provokes the hypothalamus to reply through the pituitary gland, which is just below it in the brain. The hypothalamus is therefore often seen as the interface between the nervous and endocrine systems.

The pituitary gland is in two parts with rather different modes of functioning.

The posterior pituitary is really an outgrowth of the hypothalamus and is composed of nerve tissue. It stores two peptide hormones produced by the hypothalamus until the latter sends a nerve signal telling it to secrete some. Its two hormones are oxytocin, important in child bearing and rearing, and antidiuretic, or ADH (vasopresson), which signals the kidneys to control the concentration of water in the blood.²It seems like it would be easier to refer to the posterior pituitary as the lower hypothalamus instead of a gland. That it is not may be for historical reasons.

The anterior pituitary is composed of glandular tissue and synthesizes six main peptide hormones as well as some minor ones. It too is under the command of the hypothalamus, which communicates with it by a specific set of capillaries, the hypophyseal portal system. The hypothalamus secretes four releasing hormones and two inhibiting hormones which control secretion by the anterior pituitary. The anterior pituitary, in turn, secretes six hormones which stimulate other glands to release hormones to influence bodily functions. For instance, thyroid-stimulating hormone (TSH) stimulates the thyroid gland to produce T4 and T3 hormones and these in turn control the rates of chemical reactions elsewhere. So control goes through several steps from the hypothalamus to the anterior pituitary and on to the thyroid which then tells some other organ to do its thing.

One wonders why the two parts of the pituitary are considered to be one gland instead of two organs. Maybe this is for historical reasons.

Be that as it may, the effect of most of the pituitary hormones is to stimulate other organs to produce hormones; it is a two-step control process – three, counting the hypothalamus.

The thyroid and parathyroid glands

As shown in the above figure, the thyroid gland is located in the front of the neck. Its follicles contain thyroglobulin, which contains tyrosine amino acids. Reception of TSH from the anterior pituitary gland causes active receptors on the follicle cells to transport I^– (iodide) ions into the cell, where they are oxidized to I₂. After peroxydase enzymes link them to tyrosine, the products finally form two hormones, triiodothyronine (T₃), containing three iodines, and thyroxine (T₄), containing four.³The explanation of this process given here is greatly simplified.

In a later step, low levels of T₃ and T₄ in the blood are detected by the hypothalamus, which releases TRH into the anterior pituitary gland, triggering it to release more TSH which in turn signals the thyroid gland to release its hormones into the blood stream. The same system allows the hypothalamus to stop TRH release, thus leading the thyroid to cease emission of its hormones. This feedback mechanism is shown in the figure.

Thyroid hormones are extremely important, having an effect on almost every physiological process in the body. They influence the body’s rate of basal metabolism, the rate of energy use when at rest. They accomplish this by modifying the amount of respiration-related enzymes within mitochondria, and by stimulating glycogen breakdown into glucose, the raw material for cellular respiration. Changing the metabolic rate also changes body temperature. Thyroid hormones also regulate rates of protein synthesis and so are important for growth, especially in young children. They eve influence mental processes.

Thyroid hormones depend on an adequate level of iodine in the body. Too much (hyperthyroidism) or too little (hypothyroidism) can lead to symptoms such as reduced mental activity or mental retardation, goiters (swollen thyroid gland), fertility or development problems

The thyroid also secretes calcitonin, a hormone whose role is to bring about a reduction in Ca⁺⁺ levels in the blood. Its “other half” is PTH. PTH is secreted by two to six tiny parathyroid glands on the posterior surface of the thyroid and stimulates an increase Ca⁺⁺ levels. As we have seen, this ion plays an essential role in the contraction of muscles.

The adrenal glands

The adrenal glands sit on top of the kidneys (“ad” = near, “renal” = concerning the kidney). They are in two very different parts, the adrenal cortex and the adrenal medulla. The adrenal glands are important in the body’s response to physical or psychological stress.

The adrenal cortex is the outer part of the gland and is composed of glandular tissue. It is stimulated by the hypothalamus via the anterior pituitary, called the HPA axis. The adrenal cortex plays a role in long-term stress response. Three different parts of the cortex secrete different hormones.

• The outer cortex, the zona glomulerosa, produces mineralocorticoids, which control levels of electrolytes and liquids. The most important, aldosterone, increases the amount of Na⁺ ions in the blood and the volume and pressure of the blood.
• The intermediate cortex, the zona fasciculata, produces gluticorticoids, which influence glucose metabolism. The principal one, cortisol, plays a role in stress response by making body fuel more readily available through the conversion of glycogen to glucose, the breakdown of fatty acids and glycerol, and catabolism of muscles into amino acids. It also down-regulates the immune system, which explains its use against joint inflammation, such as in hydrocortisone creams.
• The most inner cortex, the zona reticularis, produces androgens, such as testoserone.

The adrenal medulla, in the inner part, is composed of neuroendocrine tissue and can be considered an extension of the autonomic nervous system. It is stimulated by the hypothalamus via neurons in the thoracic spinal cord, the sympathomedullary (SAM) pathway. Its major role is in short-term stress, which causes the sympathetic nervous system to alert the adrenal medulla to produce catecholamines, the hormones epinephrine (perhaps better known as adrenaline) and norepinephrine (noradrenaline). These prepare the “fight-or-flight” response by converting glycogen into glucose, raising the level of blood sugar; raising the heart rate, pulse and blood pressure; diverting blood away from digestion and other less immediate functions in order to increasing the availability of oxygen; and partially down-regulating the immune system. Thyroid hormones can up-regulate catecholamine receptors in blood vessels.

Stress response may be divided into three phases called the general adaptation syndrome, or GAS:

1. The first stage is the alarm reaction, the short-term “fight or flight” response initiated by the adrenal cortex’s release of epinephrine or norepinephrine via the SAM pathway.
2. If the stress continues, the stage of resistance, or adaptation, is entered. The body tries to adapt, for instance, by reducing physical activity.
3. If the stress lasts still longer, the stage of exhaustion arrives as the adrenal cortex releases hormones via the HPA axis, as described above. Results may be depression, immune system suppression or extreme fatigue.

The pineal gland

The function of the pineal gland, a tiny gland situated inferior and slightly posterior to the thalamus, is not entirely understood. Light impinging on the retina of the eyes travels up the optic nerve to the suprachiasmatic nucleus (SCN) of the hypothalamus, which passes a signal through the spinal cord and on to the pineal gland where it inhibits the production of melatonin. This promotes wakefulness. The pineal gland therefore may influence the body’s circadian rhythms. Melatonin is used by some air travelers in an attempt to diminish the effects of changes of time-zone.

The pancreas

The pancreas is an organ with a double function. It contains exocrine cells, which release digestive enzymes directly into the small intestine. Such enzymes are essential for digestion, as we have seen in the chapter on digestion.

The pancreas also contains small structures call pancreatic islets which secrete hormones into the blood, The islets contain four types of cells.

• alpha cells produce glucagon;
• beta cells produce insulin;
• delta cells secrete somatostatin, which prevents simultaneous production of glucagon and insulin;
• PP cells produce pancreatic polypeptide hormone which plays a role in appetite and feelings of satiety.

We have already seen the important role played by glucagon and insulin in respectively raising and lowering glucose levels in the blood. They accomplish this by modulating glucose absorption and subsequent energy production by the cells (cellular respiration); the storage of glycogen in the liver (glycogenolysis); and the conversion of amino acids and glycerol into glucose (glyconeogenesis).

Endocrine functions of other organs

Other organs with endocrine functions are indicated in the table. In addition, there are a number of organs with other primary functions, but which also secrete hormones, including the heart and the skeleton. The following table covers these organs.

Organ	Major hormones	Effects
Heart	Atrial natriuretic peptide (ANP)	Reduce blood volume, pressure and Na+ concentration
Gastrointestinal tract	Gastrin, secretin, cholecystokinin (CCK)	Aid digestion, buffer stomach acids
Gastrointestinal tract	Glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide 1 (GLP-1)	Stimulate pancreatic beta cells to release insulin
Kidneys	Renin	Stimulate aldosterone release
Kidneys	Calcitriol	Aid absorption of Ca++
Kidneys	Erythropoietin	Trigger red blood-cell formation in bone marrow
Skeleton	Fibroblast growth factor 23 (FSF23)	Inhibit calcitriol production, increase phosphate excretion
Skeleton	Osteocalcin	Increase insulin production
Adipose tissue	Leptin	Promote satiety signals
Adipose tissue	Adiponectin	Reduce insulin resistance
Skin	Cholecalciferol	Modified to form vitamin D
Thymus (+ other organs)	Thymosins	Aid in T-lymphocyte production, more…
Liver	Insulin-like growth factor-1	Stimulate bodily growth
Liver	Angiotensinogen	Raise blood pressure
Liver	Thrombopoetin	Cause increase in platelets
Liver	Hepcidin	Blocks iron release into bodily fluids

Another communication pathway is the circulatory system.

The body as communications and control network

Chemical and electrochemical communications between regions and organs of the body take place constantly.

We have seen feedback processes which control certain reactions,

• allosteric binding of reaction products;
• control of lactose-digestion enzymes;
• blood sugar levels controlled by insulin and glucagon;

as well as direct communication of muscle-control signals by the ANS.

We can anticipate the next chapter, on neuroscience, and see communications at work in other ways:

• conveying sensory data input to the brain;
• control of body functions by the central and peripheral nervous systems.

In addition to these two communication methods (chemical feedback and nervous-system control), another important system exists – hormones, the subject of which constitutes what has long been called the endocrine system (ES), although it is now known that hormones are also produced elsewhere.

The nervous system (NS) receives information from sensory organs dispersed throughout the body and in turn transmits information outwards, such as to a particular muscle cell. Communication takes place at speeds on the order of 100 meters/second and so can reach any part of the body in less than 0.01 seconds. The effect of the output, such as a muscular contraction, lasts only a short time, so the action is specific, fast and short-term.

Compared to this, communication by the endocrine system is slow and less specific, but durable. Endocrine communication takes place through the transmission of chemical messengers called hormones. Hormones are chemicals which are synthesized by tissues which may exist in specific organs called glands or in tissues or organs which also have other functions, like the pancreas.

Hormones travel through the blood until they encounter cells with special receptors which match the hormone. Any such cell may be affected. What happens then depends on the hormone and on the receiving cell. Hormones influence many bodily functions at different levels.

One may imagine a metaphor based on modern telecommunications and good ol’ radio. If the nervous system is a high-speed point-to-point link, then the hormonal system is a low-speed broadcast from a point to any stations which may be tuned to that frequency.

Another metaphor is more anthropomorphic. Chemicals which permit communication are like messengers and that is what they are often called. We will meet a number of them.

The ES and the NS work together to optimize functioning of body processes.

We will look at the following subjects:

The endocrine system — hormones

The human circulatory system

The immune system

The lymphatic system

Then we will move on to neuroscience — soon.

 

The most obvious distinction between plants and animals is animals’ motility, our ability to move around whenever we feel like it.

Scientists think that the basic mechanism of motility is similar in all complex cells. This mechanism and its evolutionary origins were referred to briefly in the section on the cytoskeleton in the biochemistry chapter.

Motility of large organisms requires muscles. There are three types of muscles:

• Skeletal muscles are attached to bones by tendons and contract to produce movement of the body. They are innervated voluntarily. (This is partly a question of definition. Even when they are innervated involuntarily, the innervation is said to be voluntary.
• Cardiac muscles make the heart beat. In fact, the heart is pretty much a big muscle. The heart has its own clock, whose rate can be modified by the nervous system.
• Smooth muscles line the digestive and respiratory tracts, surround sphincters and control the opening of the iris of the eye, among other things. Their action is involuntary, triggered by hormones, the ANS and local conditions.

Let’s look at those in more detail.

Skeletal muscles

Skeletal muscles do not just make joints move. Muscles are rarely completely relaxed, but maintain muscle tone, constantly contracting and relaxing by small amounts in order to stabilize joints and maintain balance. This is brought about by complex interactions with the nervous system.

During the development of skeletal muscles, many individual cells fuse together, usually retaining their nuclei and mitochondria. Multiple mitochondria are necessary in order to supply the great amounts of energy needed by muscles. Muscles which work more and contain more mitochondria are darker colored than those which contain fewer. Chicken legs serve to walk and are dark meat; chicken wings serve little purpose and are small and light-colored.

Looking from the outside in, muscle cells consist of numerous components, one nested within another, including three layers of connective tissue, or mysia (singular mysium).

• An outer layer, the epimysium, holds the muscle together as it contracts and expands. It also connects to tendons.
• Inside the epimysium are bundles of cells called fascicles, bounded by a second layer of connective tissue, the perimysium.
• Inside each fascicle, the muscle cells themselves, called fibers, are bundled in another layer of connective tissue, the endomysium. The endomysium furnishes nutrition to the cells. Fibers can be quite long, up to 30 cm in the leg.
• The fibers in turn are bundles of elements, the myofibrils, which run the length of the fiber.

Within the fibers, skeletal muscle cell components have special names, beginning with “sarco” (Greek for “flesh”). The cell membrane is called the sarcolemma; the cytoplasm, the sarcoplasm; and the smooth endoplasmic reticulum, the sarcoplasmic reticulum (abbreviated SR)

Skeletal muscles appear to be striated (or striped) because each myofibril is composed of a series of elements called sarcomeres, which are where the action is. The sarcomeres are placed end to end along the myofibril and contain two types of filaments: thin filaments called actin and thicker ones called myosin. The actin filaments are anchored to the ends of the sarcomeres (called Z disks or Z lines) and do not meet in the middle. The myosin filaments are positioned at the mid-point of the sarcomere, called the M line, and each end is bound to the nearest Z disc by elastic bands of the protein titin, or connectin, which act like springs, allowing the sarcomere to expand and contract while maintaining its form. The actin and myosin filaments overlap partially.

The myosin filaments are composed of multiple myosin molecules wound up together. Each molecule has a head on one end and this protrudes outward from the axis of the filament. Each head has a binding site for actin on the end and another one for ATP. In fact, the myosin head functions as an ATPase enzyme and can cleave ATP to recover the energy in it. The energy is then available for powering muscular contraction.

The actin filaments, consisting similarly of wound-up cables of actin molecules, contain binding sites for the myosin heads. When the muscle is relaxed, these sites are blocked by the protein tropomyosin, which spirals around the actin and is in turn is bound with another protein, troponin.

The neuromuscular junction (NMJ) is the point at which the motor neuron from the peripheral nervous system innervates the fiber Each fiber is connected to one branch of a motor neuron axon¹An axon is the output arm of a neuron. This will be discussed in some detail in the neuroscience chapter.. If more than one fiber is connected to a neuron, the set of fibers for that neuron constitutes a motor unit. This allows for precise innervation of muscle fibers: the smaller the motor unit, the more precise the control. In the thousands of muscle fibers which move our eyeballs, a motor unit is made up of only about six fibers, making for great precision of movement. In contrast, in our back or thigh muscles, a motor unit may include thousands of muscle fibers.

When the NMJ receives an action potential, it releases the neurotransmitter acetylcholine, abbreviated Ach. Reception of Ach on the fiber receptors brings about the propagation of an action potential along the sarcolemma and through so-called T tubules to the SR, which opens calcium channels and releases Ca⁺⁺ into the cell.

In more detail, the Ach receptors contain Ach-gated cation channels which open when Ach binds to them. Since the cell is normally at a negative voltage relative to its surroundings, opening the channel lets positive ions flow through the membrane and into the cell, causing it to depolarize (become less negative). This causes the opening of voltage-gated sodium channels, so Na⁺ enters the cell and brings about an action potential. (For more information on action potentials, see the biochemistry chapter.) When the action potential crosses the T tubules and reaches the SR, the SR releases Ca⁺⁺ ions into the cell. The Ca⁺⁺ binds to the troponin, which in turn causes tropomyosin to re-configure in such a way that the myosin binding sites on the actin are unblocked.

What happens next is described by the sliding-filament model of muscular contraction. (Some details of this model are still hypothetical.)

1. The myosin heads already are bound to ADP and P_i. As the P_i is released, the myosin heads bind strongly to the actin, creating cross-bridges between the two filaments.
2. The myosin heads then execute the power stroke: They bend toward the M-line (therefore in opposite directions on each side of the M-line), dragging the actin filaments with them (about 10 nm), increasing the overlap of the two filaments and compacting the sarcomere and, hence, the muscle.
3. The myosin head now can bend no more. ATP binds to it and causes it to detach from the actin. The head, using energy from conversion of the ATP to ADP and Pi, returns to its neutral position. It now is “cocked” and ready to launch another power stroke, As long as the binding sites on the actin are unblocked the cycle can repeat.

Eventually, the original Ca++ is stored back into the SR by a membrane pump. Then the cycle stops until more Ca++ unblocks the actin binding sites.

In the sarcomere, the myosin heads drag the actin filaments along, step by step, as they overlap and the sarcomere shortens.

Energy for muscle action

Muscles need energy in order to function. This is why skeletal muscles have multiple mitochondria, energy factories. Energy can come from different sources and the muscles which use different sources differ in their type and function.

When a muscle is at rest, excess ATP produced may be transferred for storage to creatine phosphate (or phosphocreatine) in the muscle. This molecule stores energy in its phosphate bonds and can give it back very quickly, but can not store more than about 15 seconds worth of energy. So it is a fast, but short-duration source of energy.

Energy can also be obtained without the need of oxygen by anaerobic respiration through the conversion of glucose into ATP by the process of glycolysis, which we have already considered in some detail. This procedure is slower and, as we have seen, relatively inefficient.

After this, if oxygen still is not available, fermentation, already discussed, can convert pyruvate into lactic acid with a small gain in energy.

If oxygen is present, then aerobic respiration (Krebs cycle + oxidative phosphorylation), which is very efficient, provides energy. But it does require a regular supply of oxygen and is slower than glycolysis. So intense energy needs by muscles will first be supplied by phosphocreatine and then by glycolysis.

When muscles need ATP from aerobic respiration but the oxygen supply is short, then there is what is called an oxygen debt, which makes us breathe hard after an intense muscular effort.

Cardiac muscles

Heart muscles are striated like skeletal muscles, but are shorter and only have one nucleus per cell, although they still have many mitochondria. They are multi-branched and the branches are interconnected through intercalated discs. Gap junctions between fibers allow rapid transmission of action potentials for coordination of activity throughout the heart. The heart has its own clock and is not controlled by the nervous system.

Muscle contraction occurs through a sliding- filament scheme similar to the one in skeletal muscles. But cardiac muscles are autorhythmic: Their contractions are controlled by pacemaker cells within the heart itself, although the ANS²The autonomic nervous system, remember? may signal the heart to speed up or slow down. The pacemaker cells cause a group of cells, called a functional syncytium, to auto-excite and create an action potential. This subject will be covered in the next chapter.

Smooth muscles

Smooth muscles are not striated and contain no sarcomeres. They occur in many organs and body structures, including the digestive, urinary, respiratory, circulatory and reproductive systems, so they are quite wide-spread. They are fusiform in shape – thick in the middle and tapered at the ends. Their action is involuntary, triggered by hormones, the ANS and local conditions.

They too contract through a system similar to the sliding-filament scheme of skeletal muscles, but with important differences. Smooth muscles possess no troponin-tropomyosin complex. In a process beginning with Ca⁺⁺ ions binding to a protein called calmodulin, the myosin heads are activated by being phosphorylated. The heads crawl along the actin thin filament, which is attached at its ends to dense bodies, the smooth-muscle equivalent of Z discs. But this pulls on a network of intermediate filaments, which in turn contracts the whole fiber along its length, causing it to get shorter as it swells up in the middle.

So muscles can contract because of energy from oxidative respiratioin (mostly) which uses input from food which comes from … plants — by photosynthesis.

Although products of the digestion of all three food types – carbohydrates, proteins and lipids – all follow some common pathways for energy conversion, one usually attacks this subject by considering carbohydrate digestion, as this allows a linear presentation of the entire sequence – glycolysis, rhe Krebs cycle and chemiosmotic phosphorylation (the electron transport chain). Afterwards, we will consider how the other two types enter into the same processes.

Glucose is the body’s principal fuel supply and is carried by the blood to all cells. In each cell’s mitochondria, glucose is broken down by cellular respiration, a series of reactions which use various enzymes to convert the glucose into water and CO₂ and release the energy needed by metabolism. The overall reaction forming the basis of cellular respiration is

C₆H₁₂O₆ + 6O₂ → 6H₂O + 6CO₂ + energy

i.e.,

glucose + oxygen → water + carbon dioxide + energy

where the energy is principally stored in molecules of ATP, the body’s “energy currency”. ATP serves as a transport agent, carrying the energy from mitochondria to elsewhere in the cells, which need it in order to function.

There are several sets of reactions capable of breaking down glucose to store energy in ATP molecules. The three main ones are

• glycolysis,
• the Krebs cycle (or citric-acid cycle or TCA cycle) and
• oxidative phosphorylation (the electron transport chain).

Each set is called a pathway. Taken in sequence, they together are referred to as cellular respiration. This step-by-step process has two functions:

1. Ensure energy is released in small, controlled quantities; and
2. make the activation energy necessary for each step small enough to be adequately lowered by an appropriate enzyme.

Glycolysis

The first pathway, glycolysis, is a series of reactions which take place in the cytoplasm of the cell and convert one glucose molecule into two pyruvate molecules. The overall equation is:¹Coenzyme electron carriers NAD and FAD were discussed in the last chapter.

glucose + 2 ATP + 2 NAD⁺ + 4 ADP + 2 P_i → 2 pyruvate + 4 ATP + 2 NADH + 2 H⁺

Each step of this pathway (and all the others) is brought about by an enzyme.The following table indicates the steps of glycolysis in some detail.

Step	Input	Output	Enzyme
1	glucose + ATP	glucose-6-phosphate (G6P)	hexokinase (or glucokinase, if in the liver)
2	glucose-6-phosphate	fructose-6-phosphate (P6P)	glucose-6-phosphate polymerase
3	fructose-6-phosphate + ATP	fructose-1,6-biphosphate	phosphofructokinase
4	fructose-1,6-biphosphate (split)	glyceraldehyde-3-phosphate + dihydroxyacetone phosphate	aldelase
5	dihydroxyacetone phosphate	glyceraldehyde-3-phosphate	triosephosphate isomerase
End energy-consuming, start of energy-yielding phase: Glucose now converted into two glyceraldehyde-3-phosphate
6	2 glyceraldehyde-3-phosphate + 2 Pi + 2 NAD+	2 1,3-biphosphoglycerate + 2 NADH	glyceraldehyde-3-phosphate dehydrogenase
7	2 1,3-biphosphoglycerate + 2 ADP (dephosphorylation)	2 3-phosphoglycerate + 2 ATP	phosphoglycerate kinase
8	2 3-phosphoglycerate	2 2- phosphoglycerate	phosphoglycerate mutase
9	2 2- phosphoglycerate	2 phosphoenolpyruvate (PEP)	enolase
10	2 phosphoenolpyruvate + 2 ADP + 2H+ (dephosphorylation)	2 pyruvate + 2 ATP	pyruvate kinase

Step (6) is important for two reasons. First, it is the one where the P_i necessary to convert ADP into ATP comes into the action. After step (6), the P_i is no longer free and the conversion is now energetically favorable and takes place in the step (7). A similar step produces another pair of ATP molecules in step (10). Step (6) also includes the reduction of NAD⁺, whereby it collects electrons which it will carry to oxidative phosphorylation..

The glycolysis pathway is used by almost every organism on Earth, including prokaryotes, so it must have evolved very early in the history of life.

 

Notice that glycolysis does not require oxygen in order to proceed; it is an example of anaerobic respiration.

Ignoring those complex chemical names, the table shows that each step is chaperoned, so to speak, by a different enzyme. It also shows that although the overall process is to convert glucose to pyruvate, it requires two ATP to get started (input column) but produces four (output column), for a net gain of two ATP.

The Krebs cycle

Recall the overall view of cellular respiration:

C₆H₁₂O₆ + 6O₂ → 6H₂O + 6CO₂ + energy

i.e.,

glucose + oxygen → water + carbon dioxide + energy

The Krebs cycle (or citric acid cycle, or TCA, tricarboxylic acid cycle) takes place within the matrix of a mitochondrion. The pyruvate molecules formed by glycolysis in the cytoplasm of the cell pass into the mitochondrial matrix,but pyruvate can not enter directly into the Krebs cycle. It is first converted by the enzyme pyruvate dehydrogenase as follows:

• one C and two O atoms are removed as CO₂ (decarboxylation);
• the pyruvate is oxidized and its electrons serve to reduce NAD⁺ to NADH + H⁺;
• finally, coenzyme-A is added to produce acetyl-CoA, which enters the Krebs cycle.

This is shown at the top of the following figure. This step has been referred to variously as the linking step, the grooming step or the bridging step, but I prefer the preparation step – or prep step.

The steps of the Krebs cycle are the following:

1. The citrate synthase enzyme (always enzymes) joins the 2-carbon acetyl-CoA with a 4-carbon molecule of oxaloacetate to form a 6-carbon molecule, citrate (or citric acid, hence one of the names of the cycle). As it traverses the cycle, this molecule will lose carbon atoms to become once again a 4-carbon oxaloacetate molecule, which can start the cycle over again with the addition of some acetyl-CoA. But along the way, Good Things will be produced.
2. Another enzyme, aconitase, converts citrate into isocitrate by a “simple” rearrangement of its bonds.
3. A further enzyme, isocitrate dehydrogenase, oxidizes isocitrate into 5-carbon α‑ketoglutarate.²Gulp! Carbon is released as CO₂ and electrons serve to reduce NAD⁺ to NADH + H⁺, with a gain of one NADH + H⁺.
4. Yet another enzyme α‑ketoglutarate dehydrogenase converts α‑ketoglutarate into 4-carbon succynal CoA. Once again, CO₂ is released and oxidized electrons reduce NAD⁺ to NADH + H⁺, for a gain of one more NADH + H⁺.
5. The enzyme succynal CoA dehydrogenase converts succynal CoA into succinate. This reaction is exergonic and the released energy serves to form GTP, guanosine triphosphate, similar to ATP, which in turn furnishes energy to convert ADP into ATP. A different enzyme would produce ATP directly. That makes a gain of one ATP.
6. Succinate dehydrogenase converts succinate into fumarate. The oxidized electrons are passed to the electron carrier FAD which is reduced to FADH₂, so there is a gain of one FADH₂.
7. Fumarase catalyzes the addition of a water molecule to fumarate to form malate.
8. Malate dehydrogenase oxidizes malate back to oxaloacetate (back to step 1). The electrons reduce NAD⁺ to NADH + H⁺, so one more NADH + H⁺ is gained.

Note that one glucose molecule makes two pyruvates and so brings about two “turns” of the Krebs cycle. The oxidation steps in one cycle result in a gain of three NADH + H⁺, one FADH₂ and one ATP.

Chemiosmotic theory of oxidative phosphorylation – electron transport chain

The Krebs cycle may be a great advantage over glycolysis in terms of efficiency of ATP production, but the electron transport chain (ETC), where oxidative phosphorylation takes place, has them both beat hollow.³When I first read about it, I was giggling with joy. Oxidative phosphorylation takes the electrons carried by NADH and FADH₂ produced in the Krebs cycle and uses them to produce more ATP – much more.

Recall that NAD and FAD are electron carriers, picking up electrons as they are reduced to NADH and FADH₂ as follows:

NAD⁺ + 2e^– + 2H⁺ → NADH + H⁺

and

FAD + 2e^– + 2H⁺ →FADH₂

and leaving them off as they are oxidized to NAD⁺ and FAD in the opposite reactions (just invert the arrows).

In the electron transport chain the NADH and FADH₂ produced in the Krebs cycle, with the help of two coenzymes, transport electrons to the first of a series of four enzyme complexes in the inner mitochondrion membrane. Each complex is reduced as it receives an electron and oxidized as it passes it on to the next complex, somewhat like a bucket brigade (or a relay race). The electron is passed along because each successive complex is more electronegative (electron loving) than the preceding one. (One also says it goes from a complex of higher reducing potential to a lower one.) The energy produced by the redox reactions at each complex serves to pump protons across the inner mitochondrial membrane into the inter-membrane matrix.

At the end, the electrons are passed to oxygen which uses them to combine with the residual hydrogen to produce water. The left-over re-oxidized NAD⁺ and FAD can return to glycolysis and the Krebs cycle to pick up more electrons.

Here is the amazing part! The gradually built-up proton gradient becomes sufficiently strong to power an incredible-seeming object in the inner mitochondrion membrane, an enzyme called the ATP synthase. The protons passing through it actually cause it to turn and to power the combination of ADP with phosphate radicals to produce ATP in large quantities. This synthesis of ATP by adding P_i to ADP with the energy from a proton gradient is called chemiosmotic phosphorylation.⁴Gulp!

In summary, the overall function of the ETC Is to use the energy of electrons from reduced NADH and FADH₂ to pump H⁺ across the inner mitochondrial membrane into the inter-membrane matrix so that the built-up electrical potential can power the synthesis of ATP by ATP synthase.

Look at cellular respiration with the accounting data added as in the following figure The accounting is clear. Oxidative phosphorylation can produce up to 34 ATP molecules per glucose molecule entering the glycolysis pathway, for a total of 36 ATP in cellular respiration. This is where we get most of our energy.

The system exists in one form or another in all eukaryotes and serves also in photosynthesis in plants to make the energy necessary for producing glucose.

The process can be broken down into the electron transport chain (ETC), the four complexes on the left in the following figure, and ATP Synthase, the red complex on the right. We will ignore the details of the many redox reactions taking place in each complex.

Consider the electrons transported to the ETC by one NADH. Note that only complexes 1, 3 and 4 pump protons across the membrane. Complex 1 accepts electrons from NADH, complex 2, from FADH₂.

1. One NADH is oxidized by complex 1 (C1), NADH dehydrogenase, to give up two e^– and one H⁺. For each electron, two H⁺ are pumped from the matrix across the inner membrane. Various reactions take place within the complex, but we will treat it as a black box.
2. Both e^– are transferred to ubiquinone (or coenzyme Q), a mobile transfer molecule. CoQ is hydrophobic and so can move about within the membrane, by which means it delivers the e^– to complex C3, cytochrome b-c1, bypassing complex 2. The e^– are passed one at a time to cytochrome c (another mobile transfer molecule). For each e^– accepted by cytochrome c, two more H⁺ are pumped across the inner membrane. Again, more is taking place than meets the eye.
3. Cytochrome c moves back and forth along the inner side of the inner membrane and so delivers the e^– one at a time to complex C4, cytochrome c oxidase. When C4 has received four e^–, it can use them to reduce an oxygen molecule, which is therefore the last electron acceptor in the chain: The four e^–, four H⁺ and the O₂ form two water molecules, while four H⁺ are pumped across the membrane into the inter-membrane space..
4. As shown in the figure, FADH₂ delivers its e^– directly to complex C2, which does not pump H⁺. The e^– are passed to CoQ and then follow the same path as the other e-.
5. The electric potential brought about by the H⁺ inside the cell membrane drives them across the membrane through the ATP Synthase, as the membrane itself is impervious to H⁺. Three H⁺ are necessary to make one molecule of ATP.

Many such chains exist in every mitochondrion’s inner membrane, so multiple H⁺ pumps are running all the time, converting glucose and oxygen into energy stored in ATP.

Other energy sources – energy production from metabolic pathways

We have considered glycolysis, the Krebs cycle and the ETC as components of the carbohydrate metabolic pathway. But we can also get energy from lipids and proteins using parts of the same pathway.

Lipids

In a recent episode, we left lipids inside chylomicrons or other lipoproteins in the blood, or in the liver or muscles. In order to use lipids for energy, triglycerides in the liver or muscle are converted by lipolysis to glycerol and fatty acyl CoA. Acyl CoA is then carried by carnitine into the mitochondria of the cells, where, it is converted back to fatty acids, which are degraded by the cyclic process of β-oxidation. Each loop of this process converts a two-carbon segment into acetyl-CoA, shortening the chain by two carbon atoms at each cycle. The acetyl-CoA enters directly into the Krebs cycle of cellular respiration, bypassing the glycolysis stage necessary for glucose. Since the products of the Krebs cycle also feed the electron transport chain, converted lipids can furnish a lot of energy.

Compared to carbohydrates and proteins, triglycerides can furnish more than twice the energy per unit mass. So when glucose levels become inadequate, triglycerides stored in the liver or muscle are hydrolyzed to fatty acids which, again, must be transported through the blood, this time by albumins, globular proteins in the plasma. The rate of conversion and transport of fatty acids is great enough that they can be oxidized to fulfill almost all the body’s energy needs without the need of energy from carbohydrates. Most cells except brain tissue and red blood cells can get their energy from fatty acids – as long as they last.

But some cells need glucose for energy production. Red blood cells have no mitochondira for β-oxidation and fats cannot cross the blood-brain barrier to enter the brain. The brain only represents about 2% of body weight, but it consumes on the order of 20% of metabolic energy, the greater part of which is to maintain electric potentials. So the brain needs energy continuously and quickly, which explains why we tend to black out after only a few seconds lack of oxygen in the blood. If the body’s supply of carbohydrates becomes too low, the liver goes to work, converting stored glycogen back into glucose (glycogenolysis) or synthesizing glucose from lactate, pyruvate, glycerol or amino acids alanine or glutamine (gluconeogenesis). This may happen when eating mostly fats or when fasting,

The liver stores a large quantity of fatty acids, but uses only a small part of these for its own energy requirements. So when carbohydrate stores (including glycogen) are low, great use is made of fats for energy. But, due to lack of intermediary substances, the Krebs cycle slows down. Excess acetyl-CoA accumulates in the liver, where it is combined in pairs to form acetoacetic acid which is then carried by the blood to other cells. Some of it is converted to β-hydroxybutyrate and acetone, large quantities of which can be transported rapidly to cells.⁵Differences between Guyton and Hall and Openstax about the order of these two processes. Which came first, acetoacetic acid or β-hydroxybutyrate and acetone? The end result is the same. These two substances plus acetoacetic acid are collectively referred to as ketone bodies and their synthesis from fats is called ketogenesis. On arriving in cells, all three are converted back into acetyl-CoA, which enters the Krebs cycle. This Is interesting because, in such circumstances, the brain may lack energy because fats can not cross the blood-brain barrier to supply it. But ketone bodies can. So the brain goes from glucose input to ketone bodies without ever using fats. In fact, ketone bodies are produced all the time, even in a healthy body. They are not bodies, but water-soluble liquids. They are so named because one of them is acetone.

In brief, fats stored as triglycerides in the liver may be modified to ketone bodies and enter cells where they are transformed into acetyl-CoA and enter the Krebs cycle, including in the brain.

Proteins

Proteins can also contribute to energy production. While some amino acids are used to re-form proteins (biosynthesis via gene expression) which are then used or stored, some remain. Most of these are converted by deamination, removal of amino groups (-NH2) from the acids, a process occuring almost entirely in the liver. Most of the time, the amino group is transferred to α-ketoglutanate, which thereby becomes an amino acid, glutamate. A >C=O group from the α-ketoglutanate replaces the original amino group, converting the amino acid into a keto acid. So the transfer is really transamination. Here is the interesting part. The amino acid alanine is transaminated to pyruvate; aspartate, to oxaloacetate; and almost all the others, to molecules (pyruvate, acetoacetyl CoA, fumarate, succinyl CoA, oxaloacetate and α-ketoglutamate) which figure somewhere in the Krebs cycle. So all our major nutrients wind up sooner or later participating in the Krebs cycle to make ATP.1 The number of ATP molecules obtained from a gram of oxidized protein is slightly less than that from a gram of oxidized glucose.

In order to avoid its poisoning us, ammonia left over from deamination must be removed and this is carried out by the Urea cycle.

Some of the keto acids can be modified to enter the Krebs cycle, like glucose or glucose products, and so are called glucogenic; others form ketone bodies (ketogenesis) and are called ketogenic. So ketone bodies may be the product of lipids or proteins.

Excess protein can turn to fat, too. If more protein than can be used for amino acids is consumed, much of the excess is converted and stored as fat or glycogen (gluconeogenesis). From here on, it follows the course of any other fat or glycogen.

Order of use

The preferred order of nutrients for energy is simple: Carbohydrates come first. But even the glycogen stored mainly in the liver can only furnish the body in fuel for maybe a half day. If carbohydrates run out, fats and proteins start to be used, principally fats. Use of fats continues approximately linearly until they run out. At the same time, stored amino acids are converted by gluconeogenesis to glucose. When the easily-accessed amino-acid store is reduced, fat usage increases and some of this is converted to ketone bodies, which can enter the brain and supply energy to it. However, changing from a carbohydrate-rich to a fat diet may require several weeks for brain cells to switch to obtaining up to 75% of their energy from fats (via ketone bodies).

We have seen that excess carbohydrates can be transformed into fat. Although such fats from carbohydrates also can be converted to acetyl-CoA to make energy, they can never be converted back into carbohydrates.

Anaerobic respiration

As its name implies, oxidative phosphorylation is an aerobic pathway, requiring oxygen. The electron transport chain requires oxygen for the penultimate step of adding H+ ions to O2 to make water. In the absence of oxygen, this cannot take place. If oxygen is lacking, energy must be obtained differently.

Glycolysis requires no oxygen other than what is present in the initial reactants and therefore is a form of anaerobic respiration. In case of rapid, intense energy consumption by muscles, the need may be fulfilled by glycolysis, which is much faster than the Krebs cycle, but can furnish energy for only about 15 seconds. Then another energy source must be found.

There is another, much less efficient means of creating energy from pyruvate by anaerobic respiration – fermentation. One sort of fermentation exists within the body; the other, in yeasts (in bread or beer, for instance).

When oxygen is limited, lactic acid fermentation can take place.. Enzymes use electrons from NADH to reduce the pyruvate to lactic acid plus a small amount of energy. In particular, muscle cells can can do this in order to get fast (but relatively little) energy, releasing the lactic acid into the muscles. The oxidized NADH (now NAD+) can now be recycled to glycolysis.

In bread or beer, ethanol fermentation takes place. Enzymes bring about the decarboxylation of pyruvate to acetaldehyde, releasing CO2 which makes the bubbles in beer or bread. Then enzymes use electrons from NADH to reduce acetaldehyde to ethanol. The ethanol evaporates when cooking bread, but is carefully conserved in the making of beer or wine.

Regulation of glucose levels

The liver converts glucose into glycogen and stores that; it can be reconverted whenever the level of blood sugar becomes low. This function is mediated by the hormones insulin and glucagon, both produced by the pancreas but having opposite effects.

Glucose concentration in the blood needs to be within a certain limited range in order to distribute enough energy to the body, but not so much as would harm organs and tissues, especially where blood vessels are tiny, as in the retina, the body’s extremities and the kidneys. Most cells have receptors which bind insulin, causing glucose transporters in the cell membranes to allow more glucose to enter the cell for storage, thereby reducing the glucose level of the blood. Abnormally high glucose levels in the blood are a sign of diabetes, which can be due to inadequate insulin production or to the cells’ not reacting correctly to insulin presence.

If the blood glucose level becomes too low, the pancreas secretes glucagon which stimulates production of glucose from the breakdown of glycogen, from amino acids or from stored triglycerides (lipolysis).

To see how this energy is used, proceed to the chapter on muscles.

Our nutriments are composed almost entirely of three types of substances – carbohydrates (glucids, in some countries), proteins and lipids (or fats); the rest consists of small amounts of minerals and vitamins (organic nutrients required in small amounts, but which the organism cannot synthesize). The sequences of biochemical processes which constitute use of these three types of molecules are called metabolic pathways. 

The very notion of metabolic pathways is somewhat of an idealization, since science is not that simple when we look closely. In fact, as the image shows, the pathways are connected at multiple points. In addition, there are inputs of enzymes and hormones from other organs.

In addition, there are inputs of enzymes and hormones from other organs. The liver is essential in energy regulation and storage and produces bile, which is needed for digestion of fats and lipids. Bile can be stored in the gallbladder to be delivered to the duodenum (the first part of the small intestine) when needed. The pancreas secretes enzymes essential for the digestion of all three food types.

Digestion in the small intestine is similar for all three principal food types. Carbohydrates, fats and proteins are all broken down by hydrolysis, adding a water molecule to separate the long molecules into shorter ones. For a simple disaccharide represented by R’’-R, this can be represented chemically by:

R’’-R’ +H2O → R’’OH + R’H,

where the hydrolysis process indicated by the arrow requires the use of an enzyme.

Basic digestion of the three food types goes like this:

• Carbohydrates are composed of poly- and monosaccharides. These are reduced by digestion to monosaccharides, which are used for energy or stored in cells, especially liver and muscle cells.
• Proteins are polypeptide chains of amino acids, which are broken down into the separate amino acids which will be used to make more proteins.
• Fats are composed mainly of triglycerides, which are separated into fatty acids.

Different enzymes are used in the three case.

The following sections discuss digestion of each type in more detail.¹Principal source of information, Guyton and Hall (2011), chaps. 67-69.

Digestion of carbohydrates

Carbohydrates are composed mainly of sucrose, lactose, long-chain starches and cellulose. Cellulose is not digestible and just passes through the body in the form of fibers that nutritionists are so fond of.

Food is first ground by the teeth, which facilitates subsequent digestion. Ptyalin, a digestive enzyme found in saliva, begins hydrolysis. Only about 5% of hydrolysis takes place in the mouth before the food is moved by the tongue into the pharynx (throat). The epiglottis ensures that it moves past the tracheal opening and into the esophagus (a process which sometimes functions less well in older people), through which it descends into the stomach. Hydrolysis continues there until the food becomes mixed with enough gastric secretions that the mounting acidity renders the enzyme inactive. After being kneaded in acidic gastric juice, the resulting pasty chyme passes into the small intestine, which secretes mucus, hormones and digestive enzymes.

By the time food enters the small intestine, 40-50% of carbohydrates have been hydrolyzed, principally to maltose. Further digestion of carbohydrates takes place in the small intestine as pancreatic amylase, an enzyme secreted by the pancreas, breaks them down into maltose or small glucose polymers, large molecules composed of repeated subunits. Different enzymes then split these into their constituent monosaccharides, the simplest forms of carbohydrates, which are soluble and so can cross the intestinal wall to enter the blood stream and be carried to the liver.

• Maltose from starches is broken down by maltase and a-dextrinase to glucose.
• Lactose from milk is converted by lactase into glucose and galactose.
• Sucrose (table sugar) is converted by sucrase into fructose.

The products are therefore glucose (about 80%), fructose and galactose. The last two substances are converted by the liver into glucose, which is therefore the common final form of carbohydrates arriving in cells. It is either used right away for energy, being sent to the glycolytic pathway and thence to the Krebs cycle, or converted to glycogen (by the process of glycogenesis) and stored.

Glycogen is a large polymer of glucose molecules and is an efficient form for storage. Storing glycogen instead of the individual glucose molecules allows more storage without substantial modification of the cell’s osmotic pressure.²Since osmotic pressure depends on the number of molecules in a solvent. See the discussion of osmosis and related possible danger for cells in the section on water. All the body’s cells can store small amounts of glycogen, but the champions are the liver (5-8% of its weight) and the muscles (1-3%).

When the body’s glycogen storage capacity is filled, excess glucose is converted to acetyl-CoA and thence into triglycerides (lipids), which are stored in adipose tissues. Yes, too much sugar turns to fat. Fat contains ~2.5 times the energy of an equal weight of glycogen. So since much more fat than glycogen can be stored in the body, an average person stores around 150 times as much energy in fat as in carbohydrate.

Digestion of proteins

Proteins are partially broken down in the stomach by the enzyme pepsin, important because it is capable of breaking down the protein collagen in the connective tissue of meat. This enzyme prefers a pH of 2.0-3.0, which is maintained by hydrochloric acid secreted at pH 0.8 by gastric glands in the stomach. When the resulting chyme passes into the small intestine, the pancreas excretes sodium bicarbonate to lower the acidity. As in the case of carbohydrates, the pancreas contributes enzymes, pancreatic proteolytic enzymes or proteases, to the small intestine to continue the breakdown of polypeptides into amino acids, although most remain as relatively small di- or tripeptides. Finally, inside the cytosol of enterocytes³Columnar epithelial cells, i.e., cylindrical cells on the intestinal wall, whose large surface area facilitates the transfer of molecules from the intestine. on the intestinal wall, various peptidases break down what is left into single amino acids which then pass into the blood. These are carried to the cells to be used as raw materials for the construction of new proteins in ribosomes. Any remaining peptides may cause serious problems.

In order to prevent proteolytic enzymes from destroying needed bodily proteins, they exist in unactivated precursor forms called zymogens and are only turned on when needed.

Digestion of lipids

Lipids (fats) consist of triglycerides, phospholipids, cholesterol and small quantities of other substances. Lipids are necessary for the formation of cell membranes and for many functions within cells. Like carbohydrates, they can provide energy. Most ingested fats are neutral fats called triglycerides, consisting of a glycerol nucleus attached to the ends of three fatty-acid side chains. Phospholipids are composed of only two fatty acids, attached to a hydrophilic phosphate “head group”.⁴This subject was discussed in some detail in a preceding section. Cholesterol is not a fat but has chemical properties similar to those of fatty acids and is digested similarly,

Fat digestion occurs mainly in the small intestine. The problem is that fats are not soluble in water. The hydrophobic fat globules are relatively large and must be broken up by emulsification before they can be effectively acted upon by enzymes. First, fat is mixed with bile (bile salts and, especially, lecithin) with polar and non-polar parts. The non-polar parts attach to the fats, leaving their hydrophilic polar parts pointing outwards. When they are agitated, they break up to form an emulsion, a mixture of one normally non-miscible liquid in another (like well-stirred vinaigrette salad dressing, or detergent in dish water). The smaller units of the fat present a much greater surface area than before and so can be attacked by water-soluble pancreatic lipase and split into free fatty acids (FFAs) and monoglycerides (the glycerol and the attached middle fatty acid ).

Again, the products are surrounded by bile salts with their non-polar ends towards the fats and their polar ends pointing outwards into the water. They then form small spheres called micelles, globs of which are water-soluble. The micelles then ferry the FFAs and monoglycerides through the aqueous solution to the epithelial cells. Since these are also fatty, the lipids can diffuse into them, leaving the bile behind behind to form more micelles.

The same processes of hydrolization and ferrying by micelles takes place for phospholipids and cholesterol using different pancreatic lipases.

Inside the intestinal membrane, the FFAs are re-synthesized into triglycerides. The triglycerides cholesterol, phospholipids and some apoprotein B (about 9% phospholipids, 3% cholesterol and 1% apoprotein B) are packaged into tiny (0.08-0.6 microns) phospholipid vesicles called chylomicrons whic  leave the intestinal cells. They are too big for capillaries but can flow via lacteals into the lymphatic system.⁵See the chapter on the lymphatic system. The chylomicrons transport the fats and cholesterol through the aqueous lymph and then into the venous blood via the thoracic duct. From the blood, they are stored either in the liver or in adipose tissue.

Triglycerides are converted into FFAs and back because triglycerides cannot cross the intestinal cell membranes, but FFAs can. They then enter the lymphatic system. Only small amounts of water-soluble, short-chain fatty acids like butterfat can pass directly from the small intestine into the blood without making a detour through the lymphatic system.

In short, fats are emulsified by bile salts so that they can be broken up by pancreatic lipase into FFAs. FFAs can cross the intestinal membrane and are reconverted to triglycerides. In order for them to be transported in the aqueous lymphatic system, FFAs and cholesterol are enclosed in phospholipid vesicles, called chylomicrons.

In this manner, almost all ingested fats (except short-chain fatty acids) are absorbed from the intestine into the intestinal lymphatic system in chylomicrons. These then are passed through the thoracic duct into venous blood. Several types of tissues, especially skeletal muscles, adipose tissues and heart tissues, synthesize lipoprotein lipase which hydrolyzes the triglycerides from the chylomicrons. The resulting fatty acids are either used for energy or stored in the cells until needed.

After breakup of the chylomicrons and their removal by the liver, most of the lipids left in blood plasma (>95%) are in the form of tiny particles called lipoproteins, partly lipid and partly protein, which are like miniature chylomicrons. The lipoproteins may contain triglycerides, phospholipids, cholesterol or proteins. Like chylomicrons, lipoproteins serve to transport lipids in the blood. Originally, use of a centrifuge to separate their components led to the definition of four classes of lipoproteins, based on their densities

In the body, though, no centrifuge exists to distinguish among the different densities of lipoproteins. Lipoproteins sent out by the liver carry triglycerides and are referred to as VLDLs (very-low density lipoproteins), since triglycerides are lighter than water. As tissues absorb the triglycerides, the lipoproteins become denser, effectively becoming IDLs (intermediate=density) and then LDLs (low-density). LDLs serve essentially to deliver cholesterol to tissues. But HDLs (high-density) are made up of different proteins. Their function is to carry cholesterol away from tissues and back to the liver.1 Hence, the slightly incorrect practice of calling LDLs “bad cholesterol” and HDSs “good cholesterol”.

The fat intake of the world’s peoples is quite variable, being 10-15% in parts of Asia and 35-50% in western countries. Part of this is converted to triglycerides and stored.

Use of fats for energy — energy production from metabolic pathways

Compared to carbohydrates and proteins, triglycerides furnish more than twice the energy per unit mass. So when glucose levels become inadequate, stored triglycerides are hydrolyzed to fatty acids. The rate of conversion and transport of FFAs is great enough that they can be oxidized to fulfill almost all the body’s energy needs without the need of energy from carbohydrates. Most cells except brain tissue and red blood cells can get their energy from fatty acids.

In order to be used for energy, triglycerides are converted by lipolysis to glycerol and fatty acyl CoA, the latter carried by carnitine into the mitochondria of the cells. There, it is converted back to fatty acids, then degraded by the process of beta-oxidation into acetyl-CoA, which enters the Krebs cycle of cellular respiration, the products of which also feed the electron transport chain (explained shortly).

Glycerol is converted directly into a form which can enter the glycolytic pathway (glycolysis, the introductory step to the Krebs cycle).

glycerol → glycero-3-phosphate → glycolytic pathway → energy

The liver stores a large quantity of fatty acids, but uses only a small part of these for its own energy requirements. So when carbohydrate stores (including glycogen) are low, great use is made of fats for energy. But, due to lack of intermediary substances, the Krebs cycle slows down. Excess acetyl-CoA accumulates in the liver where it is combined in pairs to form acetoacetic acid which is then carried by the blood to other cells. Some of it is converted to β-hydroxybutyrate and acetone, large quantities of which can be transported rapidly to cells.⁶Differences between Guyton and Hall and Openstax about the order of these two processes. Which came first, acetoacetic acid or β-hydroxybutyrate and acetone? The end result is the same. These two substances plus acetoacetic acid are collectively referred to as ketone bodies and their synthesis from fats is called ketogenesis. On arriving in cells, all three are converted back into acetyl-CoA, which enters the Krebs cycle. This Is interesting because, in such circumstances, the brain will be lacking energy because fats can not cross the blood-brain barrier to supply it. But ketone bodies can. So the brain goes straight from glucose input to ketone bodies without ever using fats.

In brief, fats stored as triglycerides in the liver may be modified to ketone bodies and enter cells where they are transformed into acetyl-CoA and enter the Krebs cycle even in the brain.⁷See the figure, “The steps of cellular respiration”, in chapter “Making energy available“.

The preferred order of nutrients for energy is simple: Carbohydrates come first. But even the glycogen stored mainly in the liver can only furnish the body in fuel for maybe a half day. If carbohydrates run out, fats and proteins start to be used, principally fats. Use of fats continues approximately linearly until they run out. At the same time, stored amino acids are converted by gluconeogenesis to glucose, which is used. When the easily-accessed amino-acid store is reduced, fat usage increases and some of this is converted to ketone bodies, which can enter the brain and supply energy to it. However, changing from a carbohydrate-rich to a fat diet may require several weeks for brain cells to switch (mostly) to energy from fats.⁸Guyton and Hall, 2011, p. 824.

Regulation of glucose levels

The liver converts glucose into glycogen and stores that; it can be reconverted whenever the level of blood sugar becomes low. This function is mediated by the hormones insulin and glucagon, both produced by the pancreas but having opposite effects.

Glucose concentration in the blood needs to be within a certain limited range in order to distribute enough energy to the body, but not so much as would harm organs and tissues, especially where blood vessels are tiny, as in the retina, the body’s extremities and the kidneys. Most cells have receptors which bind insulin, causing glucose transporters in the cell membranes to allow more glucose to enter the cell for storage, thereby reducing the glucose level of the blood. Abnormally high glucose levels in the blood are a sign of diabetes, which can be due to inadequate insulin production or to the cells’ not reacting correctly to insulin presence.

If the blood glucose level becomes too low, the pancreas secretes glucagon which stimulates production of glucose from the breakdown of glycogen, from amino acids or from stored triglycerides (lipolysis).

Now all this energy must be made available by the process of cellular respiration.